Psychosocial stress is a major risk factor for the precipitation and exacerbation of mental illness in susceptible individuals. Understanding the neuroadaptations induced by chronic stress could afford new opportunities for therapeutic intervention for stress-related psychiatric disorders. The candidate has shown that levels of the endocannabinoid 2-arachidonoylglycerol (2-AG) exhibit a progressive increase in response to repeated stress exposure in limbic brain regions including the amygdala, and that this increase contributes stress-response habituation. In aim 1 of this proposal the candidate will determine the temporal dynamics of the 2-AG response to stress and the molecular mechanisms subserving these effects. The candidate will test the hypothesis that the stress hormone corticosterone is required for the adaptations in endogenous cannabinoid signaling to occur in response to repeated stress exposure. Although stress increases 2-AG in the amygdala, it is not known if this increase is associated with enhanced endocannabinoid-mediated synaptic signaling. In aim 2 the candidate will test the hypothesis that this stress-induced increase in 2-AG in the amygdala is associated with enhanced capacity of amygdala neurons to participate in endocannabinoid-mediated synaptic signaling. Finally, in aim 3, the candidate will test the hypothesis that stress-induced increases in 2-AG levels contribute to the behavioral dysregulation induced by chronic stress. Elucidating the stress-induced adaptations in endocannabinoids signaling could provide novel molecular targets for drug development for the treatment of affective disorders.